Purpose: This is an internally-controlled study designed to demonstrate how to best begin 3,4-diaminopyridine (DAP) treatment in patients with Lambert-Eaton Syndrome (LEMS) and how to assess the continuing need for and optimal dose of DAP in these patients. DAP is an orphan drug that has been used elsewhere in the world for over 20 years to improve strength in patients with LEMS, myasthenia gravis (MG), and congenital myasthenia syndromes. In many countries it is considered standard therapy for LEMS. The study will determine the initial dose of DAP, will validate several clinical instruments used to assess patient response to DAP, and will develop a protocol to assess patients' continuing need for DAP. Methods: Each patient serves as his/her own control. Ten patients with LEMS are being followed in the Duke Neuromuscular Clinic and who have been taking a stable dose of DAP and pyridostigmine for at least one month will be asked to participate. Patients will be hospitalized for this study for 2 weeks on the Duke GCRC. They will discontinue DAP for 2 days, and then take three different doses on 3 consecutive days. The dose which produces the best improvement in strength will then be given three times a day for 2 days. DAP will then be stopped for 2 days, and then the same dose will be given for another 2 days. Results: One patient with LEMS completed the protocol. There were no adverse events. All 3 criteria for a successful outcome of the primary objective were met, and the secondary objectives were informative. The protocol predicted the best starting dose and indicated that the patient had been taking the most appropriate dose of 3,4-diaminopyridine. This study was planned to include a total of ten patients, however, because of lack of funding, it has been cancelled.